What is Antiphospholipid Syndrome (APS)?

Antiphospholipid Syndrome (APS)

Antiphospholipid syndrome (APS) is an autoimmune thrombophilic disorder characterized by recurrent thrombosis and/or pregnancy morbidity in the presence of persistent antiphospholipid antibodies (aPL), requiring positive laboratory tests on two occasions at least 12 weeks apart for definitive diagnosis. 1

Definition and Classification

APS can present as:

• Primary APS: Occurs as an isolated condition
• Secondary APS: Associated with other autoimmune diseases, most commonly systemic lupus erythematosus (SLE) 2, 3
• Catastrophic APS (CAPS): A rare, severe variant characterized by rapid-onset widespread thrombosis leading to multi-organ failure 2, 4

Diagnostic Criteria

Laboratory Criteria

The International Society on Thrombosis and Haemostasis (ISTH) recommends testing for three key antibodies:

1. Lupus Anticoagulant (LA):

   • Must be detected using two phospholipid-dependent coagulation tests
   • Requires 3-step methodology: screening, mixing, and confirmation
   • Parallel testing in APTT and dRVVT as first-choice clotting tests 1

2. Anticardiolipin Antibodies (aCL):

   • IgG and IgM isotypes
   • Measured by solid-phase assays (ELISA or automated systems)
   • Positivity defined as >99th percentile of normal controls 1

3. Anti-β2-glycoprotein I Antibodies (aβ2GPI):

   • IgG and IgM isotypes
   • Measured by solid-phase assays
   • Positivity defined as >99th percentile of normal controls 1

Important: The same antibodies must be positive on two separate occasions at least 12 weeks apart for definitive diagnosis 1

Clinical Criteria

APS is characterized by:

1. Vascular Thrombosis:

   • Arterial, venous, or small vessel thrombosis in any tissue or organ
   • Diagnosed using objective criteria (imaging studies, histopathology) 1

2. Pregnancy Morbidity:

   • One or more unexplained fetal deaths of morphologically normal fetuses (≥10 weeks)
   • One or more premature births of morphologically normal neonates (<34 weeks) due to severe preeclampsia, eclampsia, or placental insufficiency
   • Three or more consecutive unexplained spontaneous abortions (<10 weeks) 1

3. Other Clinical Manifestations:

   • Thrombocytopenia
   • Hemolytic anemia
   • Heart valve disease
   • Renal microangiopathy
   • Neurological disorders 1, 5

Risk Stratification

The risk profile is determined by the antibody pattern:

• Triple positivity (positive for all three antibody types) carries the highest risk for thrombosis and pregnancy morbidity 1
• Double and single positivity carry progressively lower risks

Pathophysiology

APS pathogenesis involves:

• Complex interactions between aPL (particularly anti-β2-glycoprotein I), phospholipid-binding proteins, and the coagulation cascade 3, 6
• Endothelial cell activation and dysfunction
• Complement system activation
• Prothrombotic state 2, 4

Management

Thrombotic APS

• Long-term anticoagulation with vitamin K antagonists (VKAs)
  • Target INR of 2.0-3.0 for first venous events
  • Higher INR target for arterial or recurrent events 1
• Aggressive management of traditional cardiovascular risk factors
• Low-dose aspirin may be considered in high-risk patients 1

Obstetric APS

• Low-dose aspirin plus prophylactic low molecular weight heparin during pregnancy
• Continue until 6 weeks postpartum 1

Catastrophic APS

Requires a multidisciplinary approach combining:

• Anticoagulation
• High-dose corticosteroids
• Plasma exchange
• Intravenous immunoglobulin 4

Important Considerations

• Testing should ideally be done before anticoagulation is started
• If the patient is already on anticoagulants, consider pretest anticoagulant removal procedures
• Results should always be interpreted in relation to clinical symptoms 1
• Despite apparently adequate anticoagulation, the risk of recurrent thrombosis remains high 5

Future Directions

Research is ongoing in several areas:

• Harmonization of laboratory testing methods
• Investigation of lower cutoff values in pregnancy morbidity
• Role of additional antibodies like antiphosphatidylserine/prothrombin (aPS/PT) and anti-domain I (aDI) 7
• Development of targeted therapies that eliminate or neutralize pathogenic antibodies 6